Differential regional effects of methamphetamine on the activities of tryptophan and tyrosine hydroxylase

Administration of high doses of methamphetamine (METH) produces both short- and long-term enzymatic deficits in central monoaminergic systems. To determine whether a correlative relationship exists between these acute and long-term consequences of METH treatment, in the present study we examined the regional effects of METH on tryptophan hydroxylase (TPH) and tyrosine hydroxylase (TH) activities in various regions of the caudate nucleus, nucleus accumbens, and globus pallidus. A single METH administration decreased TPH activity 1 h after treatment in the globus pallidus, in the nucleus accumbens, and throughout the caudate; in the anterior caudate, the ventral-medial was more affected than the dorsal-lateral region. In contrast, TH activity was not decreased in either the caudate or the globus pallidus after a single METH administration; however, it was altered in the nucleus accumbens. Seven days after multiple METH administrations, TH and TPH activities were decreased in most caudate regions but not in the nucleus accumbens or globus pallidus. These data demonstrate that (1) the effects of METH on TPH and TH vary regionally; and (2) the short-term and long-term regional responses of TPH to METH in the caudate and globus pallidus correlated. In contrast, METH-induced acute TH responses did not predict the long-term changes in TH activity.     

The effect of halothane on the amplitude and frequency characteristics of heart sounds in children

Although continuous auscultation has been used during surgery as a monitor of cardiac function for many years, the effect of anesthetics on heart sounds has never been quantified. We determined the root mean squared amplitude and frequency characteristics (peak frequency, spectral edge, and power ratios) of the first (S1) and second (S2) heart sounds in 19 healthy children during induction of anesthesia with halothane. In all patients, halothane decreased the amplitude of S1 (R2 = 0.87 +/- 0.12) and S2 (R2 = 0.66 +/- 0.33) and the high-frequency components (>80 Hz) of these sounds. These changes were clearly audible and preceded decreases in heart rate and blood pressure. The spectral edge decreased for S1 in 18 patients (R2 = 0.73 +/- 0.24) and for S2 in 13 patients (R2 = 0.58 +/- 0.25). Peak frequency did not change. The rapidity with which myocardial depression and its associated changes in heart sound characteristics occurred confirms that continuous auscultation of heart sounds is a useful clinical tool for hemodynamic monitoring of anesthetized infants and children. Implications: Heart sound characteristics can be used to monitor cardiac function during halothane anesthesia in children. The changes occur rapidly and precede noticeable changes in heart rate and blood pressure.     

The Batten disease gene product (CLN3p) is a Golgi integral membrane protein

Batten disease (juvenile neuronal ceroid lipofuscinosis) is a recessive neurodegenerative disorder of childhood. The gene, CLN3, was recently identified and found to encode a novel 438 amino acid protein of unknown function. In order to gain insight into the function of the Batten disease protein (CLN3p), we investigated its subcellular localization. Protein constructs incorporating CLN3p fused to the green fluorescence protein or an eight amino acid peptide tag were transiently expressed in fibroblasts, HeLa and COS-7 cells. A juxtanuclear, asymmetric localization pattern was observed that correlated with the Golgi apparatus in all three cell types. However, a proportion of transiently transfected cells exhibited a punctate vesicular distribution throughout the cytoplasm in addition to or without the Golgi localization. In order to account for localization patterns arising from intracellular protein transport disruption due to exaggerated overexpression in transiently transfected cells, we isolated a stably transfected cell line expressing only one copy of the CLN3 -GFP DNA construct. Fluorescence and biochemical analyses using this cell line demonstrated that CLN3p is an integral membrane protein that localizes primarily in the Golgi apparatus. The functional implications of this finding are discussed.     

Dopamine D2-receptors regulate neurotensin release from nucleus accumbens and striatum as measured by in vivo microdialysis

The present study was undertaken to examine the role of dopamine D2-receptors in the regulation of neurotensin release. Through a modification of the methods described by Maidment et al. (Neuroscience, 45 (1991) 81-93), we have developed a highly reproducible method of measuring changes in extracellular NT in the striatum and nucleus accumbens by in vivo microdialysis in awake animals. It was observed that calcium-dependent release of NT was evoked in both structures by infusing a high concentration of potassium. In addition, systemic administration of the D2 agonist quinpirole (5 mg/kg) induced a rapid increase of approximately 200% in extracellular NT levels in the lateral caudate and 30-40% in the nucleus accumbens. Conversely, treatment with the D2 antagonist eticlopride (0.5 mg/kg) reduced extracellular NT in the medial anterior caudate and nucleus accumbens 20-30%, but had no effect in the lateral anterior caudate. These data demonstrate for the first time that D2-receptors are important in the dopaminergic regulation of extrapyramidal and limbic NT release in conscious animals.     

Multicenter clinical experience using an erbium:YAG laser for vitreoretinal surgery

PURPOSE: To evaluate the advantages, disadvantages, safety, complications, and surgical applicability of an erbium:YAG laser system for maneuvers in vitreoretinal surgery. METHODS: A prospective, consecutive trial of 68 eyes in 66 patients undergoing vitreoretinal surgery in which an erbium:YAG laser with graduated output from 0.2 to 5.0 mJ per pulse, repetition rate of 2 to 30 Hz, and equipped with a flexible fiber optic and interchangeable 20-gauge intraocular fiber optic endoprobes was used to perform specific maneuvers, including transection, incision, and ablation of membranes, retinotomy, vessel coagulation, iridectomy, and lens tissue ablation. The patients were treated in five centers in contemporary vitreoretinal surgical settings for surgical indications, including proliferative diabetic retinopathy, proliferative vitreoretinopathy, epiretinal membrane, and retinopathy of prematurity. RESULTS: One hundred seventy-four maneuvers were performed with an overall surgical efficacy rating of excellent or good in 84% of maneuvers, ranging from a high of 100% for subretinal membrane transection to a low of 25% for coagulation of blood vessels. Complications included retinal break or photocoagulative injury in 5% of epiretinal membrane incisions, minor bleeding from transected retinal vessels during 29% of retinotomies, and intraocular lens damage during two posterior capsulotomies. The most significant limitation was the cautious pace used during maneuvers near the retinal surface. CONCLUSION: The erbium:YAG laser is capable of versatile new approaches offering precise tissue cutting and ablation in vitreoretinal surgical maneuvers with a high degree of safety. The main limitation encountered was the slow speed of certain critical maneuvers near the retina.     

Ascorbyl free radical as a real-time marker of free radical generation in briefly ischemic and reperfused hearts. An electron paramagnetic resonance study

The role of free radicals in myocardial reperfusion injury remains controversial. We have developed a new method using ascorbyl free radical (AFR) as a real-time, quantitative marker of free radical generation during myocardial reperfusion. A total of 35 dogs were studied. Twelve open-chest dogs underwent either 5 minutes (n = 5) or 20 minutes (n = 7) of coronary artery occlusion and 30 minutes of reperfusion. Seven additional animals undergoing 20 minutes of coronary occlusion also received the antioxidant enzymes superoxide dismutase and catalase, beginning 10 minutes before occlusion through the end of reperfusion. Exogenous ascorbate was infused intravenously, and the concentration of AFR in the great cardiac vein was continuously measured by electron paramagnetic resonance spectroscopy. Preocclusion AFR concentration was similar in the three groups. Upon reperfusion, AFR rose significantly in each animal group (P < .05). However, the AFR rise in the 20-minute-occlusion group, 38 +/- 17%, was significantly greater than in the 5-minute-occlusion group, 27 +/- 14% (P < .002). In addition, in the animals that received superoxide dismutase and catalase, the rise in the AFR was markedly attenuated, 13 +/- 6% (P < .002). Two dogs that received ascorbate but did not undergo coronary artery occlusion/reperfusion sequences showed no change in coronary venous AFR signal, indicating the stability of the signal over time. Five dogs received ascorbate while undergoing interventions to alter coronary venous flow: intravenous saline, dobutamine, dipyridamole, and nitroglycerin. Coronary venous AFR changes were minimal despite large coronary flow alterations, indicating that the AFR signal is independent of changes in coronary venous flow.(ABSTRACT TRUNCATED AT 250 WORDS)     

Reentrainment of motor activity and spontaneous neuronal activity in the suprachiasmatic nucleus of Djungarian hamsters

Neurons in the suprachiasmatic nucleus (SCN) of the hypothalamus exhibit a daily rhythm in spontaneous electrical activity. Essentially two methods have been employed to record this circadian rhythm: (1) an in vitro brain slice technique and (2) in vivo multiunit recordings. Reentrainment of a circadian output to a shifted light:dark cycle commonly takes several cycles (depending on the amount of shift) until completed. Such a resetting kinetic has also been shown to be valid for SCN electrical activity if recorded in vivo. In an in vitro slice preparation, however, pharmacologically induced resetting is much faster and lacks transients; that is, a shift is completed within one cycle. This study was designed to probe for the presence of transients in the neuronal activity of the SCN in a brain slice preparation. The authors exposed Djungarian hamsters to an 8-h advanced or delayed light:dark cycle and monitored wheel-running activity during reentrainment. Additional groups of identically treated hamsters were used to record the pattern of spontaneous neuronal activity within the SCN using the brain slice preparation. Neuronal activity exhibited the usual rhythm with high firing rates during the projected day and low firing rates during the projected night. However, following 1 day of exposure to the 8-h advanced light:dark cycle, this rhythm disappeared in 6 of 7 slices. Rhythmicity was still absent following 3 days of exposure to the advanced light:dark cycle (n = 4). By contrast, 3 of 7 slices prepared from hamsters exposed to a delayed light:dark cycle for 3 days exhibited a daily rhythm in electrical activity. Although pharmacological agents reset the in vitro SCN neuronal activity almost instantaneously and in in vivo studies a stable phase relationship to a shifted light:dark cycle occurs gradually over several cycles, the authors did not detect either of these patterns. Such differences in resetting kinetics (e.g., rapid resetting, gradual reentrainment, temporary lack of measurable rhythmicity) may be due to (a) application of a resetting stimulus in vivo versus in vitro, (b) duration of the resetting stimulus, (c) the nature of the resetting stimulus, or (d) the recording technique employed.     

Survival on renal replacement therapy in Europe: is there a 'centre effect'?

OBJECTIVE: Survival is the ultimate outcome measure in renal replacement therapy (RRT) and may be used to compare performance among centres. Such comparison, however, is meaningless if the influences of comorbidity, age and early deaths are not considered. We therefore studied survival rates on RRT in seven centres in Europe after taking into account the influence of age, early deaths, primary renal diagnoses, and comorbidity. DESIGN: A retrospective survival analysis was carried out on 1407 patients who commenced RRT in seven centres across five European countries during a 7-year period. Patients were stratified into low-, medium- and high-risk groups based mainly on comorbidity and to a lesser extent on age at commencement of RRT. Kaplan-Meier survival and Cox's proportional hazards model were used to compare survival. RESULTS: Before risk stratification overall 2-year survival across the seven centres ranged from 60.2 to 85.3% (69.3-89.9%) after excluding early deaths) masking a range of survivals of 27.4% for the high-risk group with the worst survival to 100% in the low-risk group with the best survival. After excluding early deaths 2-year survival in the low risk groups (n=622) was greater than 90% in all centres. Multivariate analysis showed that the mortality risk increased four fold from low- to medium- and a further 1.6-fold from medium- to high-risk group. However, despite this adjustment for comorbidity and age there still remained a significant difference in survival among some centres, i.e. a 'centre effect' which ranked the centres. CONCLUSION: Risk stratification diminishes the variance in survival between centres but a centre effect remains despite adjusting for age and comorbidity. Multicentre prospective studies are urgently required to identify the reasons for this apparent centre effect.